1. Field of the Invention
This invention relates to the field of medical treatment. More particularly, this invention is directed to a method for treating malignant melanoma using a combination of IL-2 and DTIC (dimethyl-triazeno-imidazolecarboxmide).
2. Description of Related Art
Melanoma in its advanced stages is an incurable disease. Seventy-five percent of skin cancer deaths in the United States are due to malignant melanoma (Cancer Manual, Sixth Edition, (1982), American Cancer Society, Boston, p. 104). Worldwide, the incidence has been rising sharply doubling, every decade over the past 30 years.
Surgery is the only curative therapy for melanoma in its early stages, although this modality, if used aggressively for local recurrence or metastatic disease to regional nodes, is associated with only a 20%-30% cure rate. The role of surgery in advanced diseases is palliative.
Melanoma is considered radioresistant and radiotherapy is used mostly for palliation. Hormonal therapy to date has been disappointing. Chemotherapy has resulted in some partial remissions with a single agent response rate for DTIC of 24% (Roth and Kirkwood (1987) Curr Top Oncology 9(5):2-11). This agent is considered the most effective single agent for the treatment of metastatic melanoma although visceral metastases involving the gastrointestinal tract, the liver, and the brain are relatively less responsive than soft tissue disease.
The hematologic and GI toxicities vary with the DTIC dose regimen used, but antitumor schedule dependency has not been observed. Although not widely studied in melanoma, five-day continuous infusions seem to be a rational compromise with the least acute toxicity and equivalent dose responses. Multidrug combination regimens when compared in randomized prospective trials have not shown statistically significantly better response rates than DTIC alone. (De Vita, V. T., Jr., et al, eds. (1985) CANCER, Principles & Practice of Oncology, 2nd ed., p. 1406).
Although the total spontaneous regression of melanoma has been reported on rare occasions, partial spontaneous regression is a regularly recognized phenomenon. This suggests that an immunologic event occurs with regularity in the disease. Pathologists frequently describe an intense mononuclear cell infiltrate beneath many melanomas suggestive of this immune response (Cancer Rates and Risks, 3rd Ed. (1985), NIH Pub. No. 85-691:99).
Earlier studies using immunotherapy in melanoma have been disappointing. Local immunotherapy with bacille Clamette-Guerin (BCG) showed greatest response in patients with small tumor burdens limited to the dermis. Visceral metastases did not respond and there was, at best, a minor effect on survival. However, much renewed interest in this modality of therapy has been aroused by the discovery of a wide range of immunomodulatory agents. Interferon is in clinical trials and has shown definite but limited efficacy to date (Creagan, E. T., et al (1986) Cancer Treatment Rep 70(5):619-624).
For successful specific immunotherapy, the existence of immunogenic tumor associated antigen is required. This is difficult in humans because many human cancers have low immunogenicity. Although there has been some success in preparing melanoma vaccine, some studies have shown that human melanomas only rarely stimulate autologous lymphocytes. The reasons for this lack of stimulatory activity are not well understood. Some investigators have shown a suppression of lymphocyte activity by tumor-derived factors (Roth, J. A., et al (1983) J Immunol 130:303-308).
IL-2, a lymphokine that is produced by normal peripheral blood lymphocytes and induces proliferation of antigen- or mitogen-stimulated T-cells after exposure to plant lectins, antigens, or other stimuli, was first described by Morgan, D. A., et al (1976) Science 193:1007-1008. In addition to its growth factor properties reported by Morgan et al, IL-2 has been found also to modulate a variety of functions of immune system cells in vitro and in vivo.
IL-2 was initially made by cultivating human peripheral blood lymphocytes (PBL) or other IL-2 producing cell lines. See, for example, U.S. Pat. No. 4,401,756. Recombinant DNA technology has provided an alternative to PBLs and cell lines for producing IL-2. Taniguchi, T., et al (1983) Nature 302:305-310 and Devos, R., (1983) Nucleic Acids Research 11:4307-4323 have reported cloning the human IL-2 gene and expressing it in microorganisms.
U.S. Pat. No. 4,518,584 describes muteins of IL-2 in which the cysteine normally occurring at position 125 of the wild-type or native molecule has been replaced with a neutral amino acid, such as serine. These muteins possess biological activity. U.S. Pat. No. 4,604,377 issued 5 Aug. 1986 discloses an IL-2 composition suitable for reconstituting in a pharmaceutically acceptable aqueous vehicle composed of oxidized microbially produced recombinant IL-2.
Various therapeutic applications of human IL-2 have been investigated and reported by S. Rosenberg and colleagues (see, for example, Mule, J. J., et al (1984) Science 225:1487-1489, Rosenberg, S., et al (1987) New England Journal of Medicine 316(15):889-897, and U.S. Pat. No. 4,690,915 issued 1 Sept. 1987).
Combination chemotherapy using two or more anticancer drugs to treat malignant tumors in humans is currently in use in research and in the clinic. However, the reported experience with many of these regimens is modest. Combination chemoimmunotherapy consisting of doxorubicin hydrochloride and recombinant IL-2-stimulated cytotoxic lymphocytes plus recombinant IL-2 (rIL-2) showed promising results in the treatment of murine renal carcinoma (Salup and Wiltrout (1986) Cancer Res 76(7):3358-3363).
In light of the seriousness of the disease and the paucity of effective therapeutic agents to treat malignant melanomas, there exists a need to develop a therapeutically effective protocol for treatment of such melanomas.